Transforming growth factors (TGFs) are factors which can elicit a phenotypical transformation of normal cells in a reversible way. It has been shown that administration of TGFs apparently stimulates normal cells to undergo uncontrolled growth of the cells and promotes anchorage independence as measured by formation of transformed cell colonies in soft agar (1-3). Two classes of TGFs have been distinguished. TGF-.alpha. is secreted by a wide variety of tumor cells from human or rodent origin (4-7). TGF-.alpha. and epidermal growth factor (EGF) are reported to compete for the same receptor (5, 8, 9), which is phosphorylated at tyrosine residues after the binding of TGF-.alpha. or EGF (10-11). Some evidence has been presented for the presence of another receptor, specific for TGF-.alpha. (12). The anchorage independent growth triggered by TGF-.alpha. is strongly potentiated by TGF-.beta. (13, 14). This latter TGF has been detected in many normal and tumor cells (13-17) and has been purified from kidneys (18), placenta (19) and platelets (20). TGF-.beta. is not believed to bind to the EGF receptor and is believed to require EGF or TGF-.alpha. for its transforming activity or NRK cells (13-17).
The biological role of the TGFs has not been clearly elucidated. Many studies suggest that TGFs may play an important role in the transformation event. It has been shown that cellular transformation with retroviruses (21-24), SV40 (25) or polyoma virus (26) results in the secretion of TGF-.alpha.. The tight linkage of TGF secretion to cellular transformation has been indicated by transfection experiments with polyoma virus DNA, which show that introduction of the DNA segment for middle T antigen is needed and sufficient to trigger both the transformed phenotype and the TGF secretion (26). Transformation studies with a temperature-sensitive mutant of Kirsten murine sarcoma virus also indicate that TGF-.alpha. is secreted only when phenotypic transformation occurs at the permissive temperature (21). In addition, recent studies indicate that introduction of the cloned T24 bladder oncogene induces TGF production (27). The biological relevance in tumor development is also suggested by the presence of activity identified as that of TGF-.alpha. in the urine of cancer patients, in contrast to the normal controls (28-30). The assay used, however, would not distinguish the activity of other growth factors such as EGF. These and other observations suggest that TGF-.alpha. may play a role in tumor formation via an autocrine mechanism, by which the TGFs are secreted by the transformed cells and maintain and stimulate this transformed character of the same cell population (31-32). However, the potentiating effect of TGF-.beta. may be needed as suggested by the secretion of both TGF-.alpha. and -.beta. by tumor cells (14). In this way, TGF-.alpha. may be a very potent effector molecule during malignant transformation.
Heterogeneous molecular weights for TGF-.alpha. are reported for extracts and supernatants from tumor cells (5, 12, 22, 33-34) and in urine (28-30). A small species of about 7 kilodaltons has been purified from both rodent (27, 35) and human (34, 35) cell sources. Amino acid sequence analysis of this rat and mouse TGF-.alpha. shows some homology with EGF (27, 35). The reported partial polypeptide sequence of the human TGF-.alpha. shows a strong homology with the rat and murine species (35).
It has been observed that patients with metastasized renal cell carcinoma can develop a progressive decalcification of the bone, which is reflected in a humoral hypercalcemia (36). A recent study using impure protein preparations suggests that transforming growth factors (including TGF-.alpha.) may cause bone resorption in a tissue culture system (37).
TGF-.alpha. can only be produced in such limited quantity by virus transformation of cells as to be impractical for aforementioned use as a therapeutic or diagnostic reagent.